IPERTENSIONE POLMONARE PRIMITIVA
Transcription
IPERTENSIONE POLMONARE PRIMITIVA
Ipertensione polmonare Carmine Dario Vizza Centro Ipertensione Polmonare Primitiva e Forme Associate Dip. Malattie Cardiovascolari e Respiratorie Universita’ di Roma “La Sapienza” Direttore Prof Francesco Fedele e-mail : [email protected] Ipertensione polmonare: definizione emodinamica ARTERIE CAPILLARI VENE ART POLM Normale ATRIO SIN 16 mmHg 8 mmHg PVR 2-3 WU PAPm>25 mmHg a riposo e/o >30 mmHg durante sforzo (?) Pulmonary Hypertension Unit La Sapienza University oi Rome Classificazione emodinamica IP Post-capillare ARTERIE CAPILLARI ART POLM ATRIO SIN IP postcapillare26 mmHg 18 mmHg PVR 2-3 WU Pulmonary Hypertension Unit La Sapienza University oi Rome VENE Classificazione emodinamica IP Pre-capillare ARTERIE CAPILLARI ART POLM ATRIO SIN IP precapillare 35 mmHg 8 mmHg PVR > 3 WU Pulmonary Hypertension Unit La Sapienza University oi Rome VENE Pulmonary hypertension: Classification 2013 1. Pulmonary Arterial Hypertension • Idiopatic • Hereditary (BMPR-II ; ALK-1) • Drug and Toxin induced • Associated with : – Connective Tissue Disease – HIV infection – Portal hypertension – Congenital heart diseaswe – Schistosomiasis •Persitent PH in the new born 1A Veno-occlusive disease 2. PH due to left heart disease • Systolic/Diastolic dysfunction • Valvulopaties Pulmonary Hypertension Unit La Sapienza University oi Rome 3. PH due to lung disease or hypoxia • COPD • Interstiial lung disease • Breathing sleep disorders • Chronic exposure to high altitude • Developtmental lung disorders 4. Chronic Thrmoboembolic PH 5. PH with multifactorial mechanisms Hematologic disorders, Vasculitis, Sarcoidosis, Metabolic disorders (glicogenosisi) Ipertensione Polmonare: PAPm> 25 mmHg Progressiva obliterazione Delle arteriole polmonari Pulmonary Hypertension Unit La Sapienza University oi Rome Disfunzione Ventricolare destra Grave insufficienza cardiaca Approccio diagnostico e diagnostica differenziale …. Pulmonary Hypertension Unit La Sapienza University oi Rome Iter Diagnostico: diagnosi differenziale Sospetto clinico Anamnesi,Rx Torace, ECG Eco 2D- Doppler Ipertensione Polmonare Esclusione di patologie VS Invio al centro di riferimento Diagnosi Differenziale Ipertensione Polmonare Cronica Tromboembolica Pulmonary Hypertension Unit La Sapienza University oi Rome Ipertensione Arteriosa Polmonare Ipertensione Polmonare sec. Pneumpatie Rilievo ECO Doppler di Ipertensione Polmonare Ventr Sx IP Post-Capillare Anormale Normale Studio ECO contrasto Funzione respiratoria DIA, DIV Deficit Normale Mod-severo TC Alta Ris. Scintigrafia Perfusionale Lieve Polisonno grafia Normale o difetti sfumati Difetti segmentali TC Spirale o Angio IP Pneumo Botallo OSAS Ipert Art Pol Ricerca: Auto-anticorpi Capillaroscopia HIV Pulmonary Hypertension Unit ECO V Porta La Sapienza University oi Rome IPCTE-CTEPH Studio emodinamico Test Vasoreattività Strategie terapeutiche .. Pulmonary Hypertension Unit La Sapienza University oi Rome Pulmonary hypertension: Classification 2013 1. Pulmonary Arterial Hypertension • Idiopatic • Hereditary (BMPR-II ; ALK-1) • Drug and Toxin induced • Associated with : – Connective Tissue Disease – HIV infection – Portal hypertension – Congenital heart diseaswe – Schistosomiasis •Persitent PH in the new born 1A Veno-occlusive disease 2. PH due to left heart disease • Systolic/Diastolic dysfunction • Valvulopaties Pulmonary Hypertension Unit La Sapienza University oi Rome 3. PH due to lung disease or hypoxia • COPD • Interstiial lung disease • Breathing sleep disorders • Chronic exposure to high altitude • Developtmental lung disorders 4. Chronic Thrmoboembolic PH 5. PH with multifactorial mechanisms Hematologic disorders, Vasculitis, Sarcoidosis, Metabolic disorders (glicogenosisi) Approccio Terapeutico nell’ Iperetensione Arteriosa Polmonare (IAP) Fino al 1995 Trattamento Medico •Anticoagulanti • Diuretici • Vasodilatori Risultati soddisfacenti In circa 10% dei casi • Settostomia atriale con pallone • Trapianto polmonare 1995-2007 • Prostanoidi • Antagonisti recettoriali ET1 • Inibitori della PDE5 Pulmonary Hypertension Unit La Sapienza University oi Rome Trattamento chirurgico Rationale of specific PAH treatments PDE5-I Prostanoids Decreased production NO,PGI2 ET-1 Antagonists Increased production ET1 Vasodilators anti-proliferative factors Vasoconstrictor proliferative factors Pulmonary Hypertension Unit La Sapienza University oi Rome PAH specific Drugs Half-life Route Prostanoids Epopoprostenol Iloprost Treprostinil Beraprost 2-4 min 20-40 min 4-6 ore 40-120 min i.v. i.v./inhal s.c. os ET-1 Antagonists Bosentan Ambrisentan 360-480 min 9-15 ore os os PDE-5 Inhibitors Sildenafil Tadalafil Pulmonary Hypertension Unit La Sapienza University oi Rome 180-240 min 36-40 ore os os Prostanoidi Epoprostenolo (emivita 2-4 min) Effetti sistemici - Dolori muscolari - Diarrea - Flush cutaneo Pulmonary Hypertension Unit La Sapienza University oi Rome Treprostinil Iloprost (emivita 4-6 ore) (emivita 20-40 min) Infezioni Frequenti Inalazioni Broncospasmo PAH specific Drugs Half-life Route Prostanoids Epopoprostenol Iloprost Treprostinil Beraprost 2-4 min 20-40 min 4-6 ore 40-120 min i.v. i.v./inhal s.c. os ET-1 Antagonists Bosentan Ambrisentan 360-480 min 9-15 ore os os PDE-5 Inhibitors Sildenafil Tadalafil Pulmonary Hypertension Unit La Sapienza University oi Rome 180-240 min 36-40 ore os os PAH specific Drugs Half-life Route Prostanoids Epopoprostenol Iloprost Treprostinil Beraprost 2-4 min 20-40 min 4-6 ore 40-120 min i.v. i.v./inhal s.c. os ET-1 Antagonists Bosentan Ambrisentan 360-480 min 9-15 ore os os PDE-5 Inhibitors Sildenafil Tadalafil Pulmonary Hypertension Unit La Sapienza University oi Rome 180-240 min 36-40 ore os os Short-term Efficacy on 6-min walk distance Epoprostenol Mean change in the 6 ’WD (m) 80 PPH 81 pts SSc 111 pts 60 Active Tx 40 20 0 -20 Control -40 Tx effect + 47 m + 108 m + 25 m + 18 m + 36 m + 44 m + 37 m + 47 m + 46 m + 33 m P value < 0.003 < 0.001 0.036 0.004 Open trials Pulmonary Hypertension Unit La Sapienza University oi Rome 0.005 0.0002 0.001 Double-blind trials 0.001 0.001 0.001 Short-term Efficacy on Pulmonary Vascular Resistance Epoprostenol Mean change in PVR (mmHg/L) (PPH) (Scl) 8 6 Control 4 2 # 0 -2 -4 Active Tx Tx effect- 4.9 - 5.5 P value <0.001 < 0.001 -1.6 -4.7 ns 0.001 PulmonaryOpen Hypertension trials Unit La Sapienza University oi Rome -4/-1.1 - 5.1 - 3.3 0.01 / ns <0.001 <0.001 Double-blind trials -2.6 -1.5 -2 -3.2 -2.6 <0.01 0.01 0.001 0.05 Mean change in Cardiac Index (L/min/m2) Short-term Efficacy on Cardiac Index Epoprostenol (PPH) (Scl) 0,8 0,6 Active Tx (CO) 0,4 0,2 0 # -0,2 -0,4 Control Tx effect +0.5 + 0.6 + 0.2 +0.18 0.01 0.01 ns 0.003 P value Pulmonary Hypertension Unit Open trials La Sapienza University oi Rome +0.75/0.25 + 1.0 0.001 0.001 + 0.4 + 0.3 + 0.23/0.26/0.4+ 0.36 0.001 0.01 ns/0.03/0.001 0.05 Double-blind trials Reduction in short-term mortality Mortality Reduction 43% (p=0.023) after 12-16 wks of active treatment Pulmonary Hypertension Unit La Sapienza University oi Rome I nuovi farmaci… Pulmonary Hypertension Unit La Sapienza University oi Rome Macitentan….. In vitro data Log D (Distribution coefficient) Lipid:Aqueous Macitentan Bosentan Ambrisentan 800:1 20:1 1:2.5 Blood Membrane Tissue • The distribution coefficient (Log D) defines the distribution of a compound between an aqueous and a lipid phase • A greater affinity for the lipid phase may favour tissue penetration • Macitentan may have a greater affinity for the lipid phase compared with other ERAs* Pulmonary Hypertension Unit La Sapienza University oi Rome Iglarz M, et al. J Pharmacol Exp Ther 2008; 327:736-45. Seraphin Study Multicentre, double-blind, randomised, placebo-controlled, parallel-group, event-driven, phase III clinical trial Macitentan 10 mg Macitentan 3 mg Screening 28 days Placebo Variable double-blind treatment duration (event-driven) Randomisation May 2008 - December 2009 End of study (EOS; 285 events) March 2012 Patients were censored at end of double-blind treatment Pulmonary Hypertension Unit Pulido T, et al. N Engl J Med 2013; 369: 809-18. La Sapienza University oi Rome Primary endpoint: Morbidity and mortality Patients without the event (%) 100 Risk reduction of primary endpoint event vs placebo 80 Macitentan 10 mg: 45% 60 Macitentan 3 mg: 30% 40 Treatment difference Macitentan 10 mg 20 Macitentan 3 mg Placebo 3 mg 10 mg Hazard ratio (HR) 0.70 0.55 Log-rank p-value 0.01 < 0.001 0 0 6 12 18 24 30 36 Patients at risk Time from treatment start (months) 242 208 187 171 155 91 250 213 188 166 147 80 250 188 160 135 122 64 Pulmonary Hypertension Unit La Sapienza University oi Rome 41 32 23 Macitentan 10 mg Macitentan 3 mg Placebo Pulido T, et al. N Engl J Med 2013; 369: 809-18. Morbidity and mortality in patients on background PAH therapy Patients without the event (%) 100 80 Risk reduction of primary endpoint event vs placebo 60 Macitentan 10 mg: 38% Macitentan 3 mg: 17% Treatment difference 3 mg 10 mg Hazard ratio (HR) 0.83 0.62 Log-rank p-value 0.27 0.009 40 Macitentan 10 mg 20 Macitentan 3 mg Placebo 0 0 6 12 18 24 30 36 Patients at risk Time from treatment start (months) 154 134 119 107 97 53 164 139 125 107 91 51 154 122 106 90 80 40 Pulmonary Hypertension Unit La Sapienza University oi Rome 24 19 10 Macitentan 10 mg Macitentan 3 mg Placebo Pulido T, et al. N Engl J Med 2013; 369: 809-18. Riociguat….. sGC GTP sGC cGMP GTP GTP GTP cGMP cGMP GTP cGMP GTP •cGMP, cyclic guanosine monophosphate; GTP, guanosine triphosphate; NO, nitric oxide; sGC, soluble guanylate cyclase. Pulmonary Hypertension Unit •Stasch J-P & Hobbs AJ. Handb Exp Pharmacol 2009;191:277–308. Stasch J-P et al. Circulation 2011;123:2263–73. La Sapienza University oi Rome Ghofrani HA et al. Future Cardiol 2010;6:155–66. Schermuly R et al. Expert Opin Invest Drugs 2011;20:567–76. Riociguat: PATENT study Placebo-corrected treatment effect = 36 m (95% CI: 20–52 m; p<0.0001) 40 Mean change from baseline in 6MWD (m) n=241 n=233 n=235 n=243 30 * n=254 n=247 20 n=111 10 n=116 n=117 n=112 n=121 0 Riociguat Placebo -10 0 2 * 4 * n=126 Observed Imputed 6 Week 8 10 12 •Last visit = last observed value (not including follow-up) for patients who completed the study or withdrew, except imputed worst value (zero) in case of death or clinical worsening without a termination visit or a measurement at that termination visit. 6MWD, 6-minute walking distance. Pulmonary Hypertension Unit La Sapienza University oi Rome 29 •Ghofrani HA et al. N Engl J Med 2013. In Press. Riociguat Primary endpoint: entire population (n=254/126) Naïve population (n=123/66) +38 m (95% CI: 15–62 m) +36 m p<0.0001 (95% CI: 20–52 m) Pretreated population (n=131/60) +34 m (95% CI: 15–56 m) •6MWD, 6-minute walking distance. Unit •GhofraniPulmonary HA et al. N EnglHypertension J Med 2013. In Press. La Sapienza University oi Rome 30 Riociguat: secondary endpoints Parameter Riociguat vs placebo; p value PVR <0.0001 NT-proBNP <0.0001 WHO FC 0.0033 Time to clinical worsening 0.0046 Borg dyspnea score 0.0022 EQ-5Da 0.0660 LPHa 0.0019 •aHierarchical testing. •EQ-5D, EuroQol Group 5-Dimension Self-Report Questionnaire; LPH, Living with Pulmonary Hypertension questionnaire; •NT-proBNP, N-terminal prohormone of brain natriuretic peptide; PVR, pulmonary vascular resistance; WHO FC, World Health Organization functional class. Pulmonary Hypertension Unit La Sapienza University oi Rome 31 •Ghofrani HA et al. N Engl J Med 2013. In Press. Treatment algorithm 2013: General measures and Hemodynamic Pulmonary Hypertension Unit La Sapienza University oi Rome Treatment algorithm 2013: Specific PAH treatment Pulmonary Hypertension Unit La Sapienza University oi Rome Cosa ci dobbiamo aspettare quando cominciamo una monoterapia orale ? Pulmonary Hypertension Unit La Sapienza University oi Rome Clinical Worsening in Bosentan-Treated Patients with iPAH Breath-1 NEJM 2002 Mc Laughlin ERJ 2005 Provencher Thorax 2005 Pulmonary Hypertension Unit La Sapienza University oi Rome Vizza CD, et al. Int.J:Cardiol 2012. 26;589-595. Clinical worsening in PDE5-I treated patients Patients without the event (%) 100 80 40% 60 Placebo (PDE5-I) 40 Macitentan 10 mg 20 Placebo 0 0 6 12 18 24 30 Patients at risk Time from treatment start (months) 154 134 119 107 97 53 164 139 125 107 91 51 154 122 106 90 80 40 Pulmonary Hypertension Unit La Sapienza University oi Rome 36 24 19 10 Macitentan 10 mg Macitentan 3 mg Placebo Pulido T, et al. N Engl J Med 2013; 369: 809-18. Pulido T, et al. N Engl J Med 2013; 369: 809-18. Treatment algorithm 2013: When to combine Pulmonary Hypertension Unit La Sapienza University oi Rome Scheduling the examinations…. Baseline 1° month 4-6 month NYHA X X X EKG X X X Walk Test X X X SpO2 Rest/Ex X X X DLCO X ECHO X MRI X CPX X Cath study X (X) Biomarkers X (X) Pulmonary Hypertension Unit La Sapienza University oi Rome 1 year Clinical judgement (X) X X X (X) X X X X X X Dovremmo trattare i pazienti in maniera più aggressiva ? Pulmonary Hypertension Unit La Sapienza University oi Rome Impact of RV EF and PVR changes after therapy on survival Pulmonary Hypertension Unit La Sapienza University oi Rome van de Veerdonk M. J Am Coll Cardiol 2011;58:2511–9 Up-front combination therapy ? Pulmonary Hypertension Unit La Sapienza University oi Rome Upfront triple combination therapy : Effect on haemodynamics Prospective, observational analysis of idiopathic or heritable PAH patients (n = 10) treated with upfront combination therapy (epoprostenol, bosentan and sildenafil) Baseline 4-month Last visit (12-28 months) 10 7 5 13 ± 6 6 ±7 6 ±5 mPAP (mmHg) 68 ± 17 45 ± 13* 48 ± 10* PCWP (mmHg) 8 ±3 7 ±3 7 ±4 1.6 ± 0.4 3.7 ± 0.4 ‡ 3.2 ± 0.4 ‡ 1798 ± 713 461 ± 134 ‡ 563 ± 188 ‡ Heart rate (bpm) 92 ± 13 85 ± 13 84 ± 10 BP (mmHg) 90 ± 14 79 ± 10 97 ± 27 SvO2 (% ) 48 ± 10 70 ± 3 ‡ 74 ± 4 ‡ n RAP (mmHg) CI (l/min/m2 ) PVR (d.s.cm-5 ) Pulmonary Hypertension Unit La Sapienza University oi Rome Sitbon O, et al. Am J Respir Crit Care Med 2011; 183:A5910. Upfront triple combination therapy in IPAH 100% p = 0.047 80% Survival 60% 40% 20% Triple combination therapy group Matched control group 0% 0 Patients, 18 at risk (n) 35 Pulmonary Hypertension Unit La Sapienza University oi Rome 12 24 36 Time, months 48 60 17 11 8 2 Triple Rx 31 26 18 7 Control Data from University Paris-Sud, France. Slide courtesy of Olivier Sitbon. In summary … Epoprostenol monotherapy (n=46) Epoprostenol + bosentan combination therapy (n=23) Epo + bosentan + sildenafil combination therapy (n=17) 2000 2000 2000 1600 PVR (d.s.cm-5) PVR (d.s.cm-5) PVR (d.s.cm-5) 1500 1500 1000 1000 1200 800 500 500 400 0 0 Baseline 4-mo. -29 ± 17% Pulmonary Hypertension Unit La Sapienza University oi Rome Baseline 4-mo. -48 ± 17% 0 Base Baseline 44-mo. mois - 69 ± 8% Courtesy Olivier Sitbon AMBITION – Study design Combo AMB+TAD PAH Rand WHO FC II-III 2:1:1 N=500 Mono AMB+PBO Mono TAD+PBO Drug titration Combination arm Monotherapy arm W0 to W4 W4 to W8 > W8 AMB 5 mg TAD 20 mg AMB 5 mg TAD 40 mg AMB 10 mg TAD 40 mg AMB 5 mg PBO PBO TAD 20 mg AMB 10 mg PBO PBO TAD 40 mg 105 events 1° EP AMBITION – Primary end-point Time to clinical failure Death (all cause) Hospitalisation for worsening PAH non-elective hospitalisation (CW) lung transplantation atrial septostomy initiation of prostanoid therapy Disease progression Decrease in 6MWD > 15% vs base With FC III-IV (2 visits >14 days) Unsatisfactory long-term response Pulmonary Hypertension Unit La Sapienza University oi Rome ALL > 6 months on therapy Disease progression Sustained FC III-IV > 6 months AMBITION: results Mean randomised treatment duration was 78.6, 66.6 and 71.6 weeks, respectively Ambrisentan + Tadalafil Reduction 50% (HR 0.502 95% CI: 0.348, 0.724; p=0.0002) of clinical events Combo was superior to each individual Mono (p<0.01), Pulmonary Hypertension Unit La Sapienza University oi Rome ERS 2014 AMBITION: results Pulmonary Hypertension Unit La Sapienza University oi Rome ERS 2014 Treatment algorithm 2015 ???? Up-front Ambrisentan-tadalafil Up-front Triple Pulmonary Hypertension Unit La Sapienza University oi Rome Considerazioni conclusive • L’utilizzo di trattamenti specifici per l’ipertensione arteriosa polmonare ha condotto ad un miglioramento della sopravvivenza (+ 10-15% annuo) • Attualmente l’approccio consigliato è una terapia di combinazione sequenziale in caso di mancato raggiungimento dei target terapeutici • Sta emergendo l’efficacia di terapia di combinazione upfront • E’ fondamentale adottare una strategia terapeutica aggressiva che contempli l’uso dei prostanoidi parenterali • Necessaria collaborazioni tra diversi centri per uniformare gli approcci diagnostici-terapeutici Pulmonary Hypertension Unit La Sapienza University oi Rome Classificazione Ipertensione Polmonare 3° Revisione 2008 – Dana Point 1. Ipertensione Arteriosa Polmonare • Idiopatica • Ereditaria (BMPR-II ; ALK-1) • associata a : – Malattie del connettivo – Infezione HIV – Ipertensione portale – Anoressizzanti – Cardiopatie congenite – Schistosomiasi - Anemia emolitica cronica • Ipertensione persistente neonato 1A. IAP + venule/capillari 2. IP secondaria a cardiopatie sin • Sistolica/Diastolica • Valvulopatie Pulmonary Hypertension Unit La Sapienza University oi Rome 3. IP secondaria a pneumopatie/ipossiemia • BPCO • Interstiziopatie • Apnee notturne • Esposizione cronica altitudine • Alterazioni dello sviluppo 4. IP cronica tromboembolica • Ostruzione prossimale • Ostruzione distale • Embolia non trombotica 5. Miscellanea • Malattie Ematologiche, Vasculiti, Sarcoidosi, Tesaurismosi (Gaucher) CHRONIC THROMBOEMBOLIC PULMONARY HYPERTENSION: SURGICAL TREATMENT TYPE OF OPERATION • Median sternotomy • Cardio Pulmonary Bypass • Deep hypotermia (16-18ºC) • Circulatory arrest (25 min) • Reperfusion period (10 min) • Bilateral J Thorac Cardiovasc Surg 1993;106:116-27 Pulmonary Hypertension Unit La Sapienza University oi Rome A. D’Armini – Policlinico S. Matteo Pavia Ipertensione Polmonare Cronica Tromboembolica – Trattamento Chirurgico P.A. – 66 yrs M – Jun 2001 – PEA #60 Base PAPm CI PVR Pulmonary Hypertension Unit La Sapienza University oi Rome 50 1.4 1385 3 mesi EAP 15 2.2 293 A. D’Armini – Policlinico S. Matteo Pavia Riociguat in CTEPH: studio CHEST Adverse event 1 (0.2%) Death 4 (0.9%) Not eligible 165 (37%) Withdrawal of consent 15 (3.4%) Screened n=446 Randomized and treated n=261 Riociguat individual titration n=173 Adverse event 4 (2.3%) Death 2 (1.2%) Lack of efficacy 2 (1.2%) Non-compliance 1 (0.6%) Protocol violation 2 (1.2%) Withdrawal of consent 2 (1.2%) Not completed n=13 (8%) Completed treatment n=160 (92%) Unit •GhofraniPulmonary HA et al. N EnglHypertension J Med 2013. In Press. La Sapienza University oi Rome Placebo n=88 Adverse event Death Lack of efficacy 2 (2.3%) 2 (2.3%) 1 (1.1%) 1 death during follow-upa Not completed n=5 (6%) Completed treatment n=83 (94%) End-point primario: test della marcia Primary endpoint: entire population (n=173/88) Population with persistent/ recurrent PH after PEA (n=52/20) +27 m (95% CI: -10–63 m) +46 m p<0.0001 (95% CI: 25–67 m) Inoperable population (n=121/68) +54 m (95% CI: 29–79 m) •6MWD, 6-minute walking distance; PEA, pulmonary endarterectomy. Pulmonary Hypertension Unit La Sapienza University oi Rome •Ghofrani HA, D'Armini A, Grimminger F et al. N Engl J Med 2013. End points secondari Secondary endpoints - Pulmonary vascular resistance (PVR) (p<0.0001), - N-terminal prohormone brain natriuretic peptide (NT-pro BNP) (p<0.0001), - WHO functional class (FC) (p=0.0026), - Borg dyspnea score (p=0.0035) - A trend in Time to clinical worsening (TTCW) (p=0.17) Pulmonary Hypertension Unit La Sapienza University oi Rome PH Unit La Sapienza, University of Rome Coordinator Carmine Dario Vizza PH clinicians (Cardiology ward, CCU, consultation & outpatients management): Senior Cardiologists Dr Vizza, Dr Badagliacca Dr. Poscia Fellows: Dr Gambardella, Dr. Pezzuto, Dr Papa, In Training: Dr Mezzapesa, Dr Nocioni Echo Lab Dr. Sciomer Dr. Badagliacca PFTs-CPX Lab Prof. Palange Dott.Valli Reumathologists Prof Valesini Prof.Riccieri Pulmonologists Prof. Parola Pulmonary Hypertension Unit La Sapienza University oi Rome CT & RNM Lab Dott. Carbone Dott. Francone Liver Transplant Unit Prof. Rossi Prof. Corradini Right Cath Lab Dott. Mancone Dott. Stio HIV clinic Prof.Vullo Lung Transplant Program Prof.Venuta